The macrolactones of formula (1) and (2) are known under different names depending on their origins (table).
______________________________________ Formula (1) Formula (2) ______________________________________ pristinamycin PIIA pristinamycin IIB mikamycin A ostreogrycin A ostreogrycin G streptogramin A synergistine A1 vernamycin A virginiamycin M1 virginiamycin M2 ______________________________________
These molecules possess the general structure of polyunsaturated macrolactones which is found in antibiotics of the streptogramin family. These antibiotics indeed consist of the synergistic combination of a polyunsaturated macrolactone (component of group A) and a depsipeptide (component of group B). The mode of action and the antimicrobial activity of these antibiotics have been studied by various authors (Tanaka et al. Antibiotics vol. III p. 487, Springer Berlin, 1975; Vasquez et al. Antibiotics vol. III p. 521, Springer Berlin, 1975).
It emerges, in particular, from these various studies that a better synergy is obtained when only the macrolactone (1) is used as component of group A.
Moreover, one characteristic of the polyunsaturated macrolactones of the group A streptogramins is that of being barely soluble in an aqueous medium. This constitutes a major drawback in the pharmacological development of these molecules since their modes of administration are as a result very limited.
In order to overcome this disadvantage, a new generation of water-soluble semisynthetic derivatives has been developed (EP 135410; EP 191662; U.S. Pat. No. 4,775,753). The semisynthesis route used consists essentially of the addition of thiol to the unsaturated bond in 2-3 of the dehydroproline of macrolactones. However, given the structure of macrolactones, only the macrolactone (1) may be used in this semisynthesis route.
However, in current production systems, the macrolactones of formula (1) and (2) are synthesized simultaneously, and mixed with other streptogramin components.
It is therefore important to be able to increase the proportion of compound (1) relative to compound (2) in the production media.
It is also important to be able to upgrade the compounds (2) which are co-synthesized with the compound (1), and isolated from the fermentation broth at the same time.
Recently, Purvis et al. raised the possibility that the macrolactone (2) is an intermediate in the biosynthesis of the macrolactone (1) (J. Am. Chem. Soc., 1989, 111, 5931). However, nothing in this document describes or gives means for exploiting this reaction mechanism.
The Applicant has now shown that it is possible to convert, at high levels, the macrolactone (2) to macrolactone (1) by means of a microorganism or an acellular preparation derived from it.